Human serum albumin (HSA)-fusion technology is a well-established technology utilized to improve efficacy, bioavailability and safety of therapeutically relevant polypeptides. Access to this technology allows CoGenesys to develop novel long-acting biologics to serve unmet medical needs. The scientists at CoGenesys have extensive experience in HSA-fusion technology, having been involved in development of more than 25 novel HSA-fusion proteins.

The development of protein and peptide therapeutics is often challenging due to their short half-lives and complex manufacturing processes. These problems may be overcome by modifying these molecules with a stable partner to generate long-acting versions. Human serum albumin (HSA) is an attractive fusion partner because it is the most prevalent naturally occurring blood protein and it has a half-life in the human body of more than two weeks. The safety of albumin itself has been well established and it is frequently used as a stabilizing agent in pharmaceutical product formulations. HSA lacks potentially confounding enzymatic or immunologic functions, is widely distributed in vivo and is a natural carrier protein in blood. The HSA-fusion technology enables development of protein and peptide-based pharmaceuticals by addressing issues of pharmacokinetics, safety, and manufacturing. In combination, the albumin fusion technology provides a versatile drug development platform able to create commercially attractive protein-based therapeutics for a wide array of indications.

The HSA fusion technology provides a unique opportunity to develop more stable versions of protein and peptide drugs currently on the market, those in late clinical development, and novel peptide and protein drug candidates whose therapeutic potential can only be realized through stabilization with HSA. Results with albumin-fusions currently in clinical studies illustrate the potential advantages of Albumin fusion proteins in terms of safety, efficacy and convenience. HSA-fusion proteins are generated by creating a genetic fusion of the polypeptide of interest with human serum albumin using recombinant DNA technology. Candidate polypeptides can be fused at either the N- or C-terminus of HSA, or both.

Figure 1. Direct gene fusion between HSA and polypeptide results in a recombinant protein.

CoGenesys has established the infrastructure and know how necessary to produce fusion proteins at clinical scale in both microbial and mammalian expression systems. A specialized Saccharomyces cerevisiae host is commonly used to produce non-glycosylated versions the HSA-fusion molecules. If a glycosylated fusion-protein is desired, the protein can produced in mammalian systems, such as CHO or NS0 cells. CoGenesys has developed an efficient, scalable and adaptable manufacturing platform for the cGMP production of HSA-fusion proteins.

Technology Validation

The albumin fusion platform is a clinically validated technology, which has a proven track record of enabling rapid development of biopharmaceutical products that demonstrate safety, efficacy and clear market value in large Phase 2 clinical trials. The most advanced albumin fusion product, Albuferon™, currently being developed by Human Genome Sciences and Novartis

A second albumin fusion product, GSK716155, is being developed by GlaxoSmithKline. GSK716155 is an albumin fusion protein based on the anti-diabetic peptide GLP-1 and is currently in clinical trials.

The HSA-fusion technology has been used to produce long-acting versions of human growth hormone (Albutropin™), IL-2 (Albuleukin™), GCSF, erythropoietin , and interferon-beta. Each of these proteins have shown promising activity profiles in preclinical and or clinical testing and has a very long half-life.

The HSA-fusion technology also exhibits a powerful demonstration of prolonging the half-life of small bioactive peptides. In general, peptide drugs have to be administered to patients frequently (or by continuous infusion) due to their rapid clearance from circulation. Many bioactive peptides long known for their potential beneficial pharmacologic action have not been further developed due to their very short serum half-life. The HSA-fusion technology has been used successfully to produce long-acting versions of numerous peptides including GLP-1, BNP, PTH and others.

CoGenesys will use the HSA-fusion technology to improve both clinically validated and other well-characterized bioactive proteins and peptides with the goal of rapid evaluation for clinical safety and efficacy. There are more than 40 marketed peptides worldwide, approximately 270 peptides in clinical testing, and about 400 in advanced preclinical phases. Classes of potential peptide-based therapeutics include enzyme inhibitors, peptide hormones and antimicrobial peptides. Recent clinical successes of parathyroid hormone (PTH, Forteo® *) for osteoporosis, exenatide (exendin-1, Byetta® **) for diabetes and Fuzeon® *** for HIV treatment have propelled therapeutic peptides toward an exciting future, but in each of these cases (and many others) the short half lives of these molecules and additional manufacturing challenges significantly limit the commercial potential of these and other bioactive peptides.

Long-acting peptide agonists of blockbuster drugs such as, erythropoietin and GCSF are also attractive opportunities. CoGenesys is considering a variety of HSA-fusion peptides and proteins for a number of disease indications, including but not limited to following:

• Cancer
• Cardiovascular diseases
• Metabolic diseases
• Infectious diseases
• Autoimmune diseases
• CNS diseases

* Forteo is a registered trademark of Eli Lilly and Company
** Byetta is a registered trademark of Amylin Pharmaceuticals Inc.
*** Fuzeon is a registered trademark of Hoffman LaRoche, Inc.